title: Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening.
abstract: We screened 124 genes that are amplified in human hepatocellular carcinoma (HCC) using a mouse hepatoblast model and identified 18 tumor-promoting genes, including CCND1 and its neighbor on 11q13.3, FGF19. Although it is widely assumed that CCND1 is the main driving oncogene of this common amplicon (15% frequency in HCC), both forward-transformation assays and RNAi-mediated inhibition in human HCC cells established that FGF19 is an equally important driver gene in HCC. Furthermore, clonal growth and tumorigenicity of HCC cells harboring the 11q13.3 amplicon were selectively inhibited by RNAi-mediated knockdown of CCND1 or FGF19, as well as by an anti-FGF19 antibody. These results show that 11q13.3 amplification could be an effective biomarker for patients most likely to respond to anti-FGF19 therapy.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Sawey
authors.forename: Maia
authors.initials: M
authors.lastname: Chanrion
authors.forename: Chunlin
authors.initials: C
authors.lastname: Cai
authors.forename: Guanming
authors.initials: G
authors.lastname: Wu
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Alice
authors.initials: A
authors.lastname: Zhao
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Herman
authors.initials: H
authors.lastname: Yee
authors.forename: Lincoln
authors.initials: L
authors.lastname: Stein
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: French
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.forename: Scott
authors.initials: S
authors.lastname: Powers
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D006801:Humans; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C117476:FGF19 protein, human; D015513:Oncogene Proteins; D019938:Cyclin D1; D005346:Fibroblast Growth Factors